WO1997049684A1 - Reactif se fixant au facteur vii - Google Patents

Reactif se fixant au facteur vii Download PDF

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Publication number
WO1997049684A1
WO1997049684A1 PCT/DK1997/000275 DK9700275W WO9749684A1 WO 1997049684 A1 WO1997049684 A1 WO 1997049684A1 DK 9700275 W DK9700275 W DK 9700275W WO 9749684 A1 WO9749684 A1 WO 9749684A1
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compound
mammal
pharmaceutical composition
treatment
factor
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PCT/DK1997/000275
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English (en)
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Lars Christian Petersen
Ole Hvilsted Olsen
Stefan Lutz Richter
Palle Jakobsen
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Novo Nordisk A/S
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Priority to AU31668/97A priority Critical patent/AU3166897A/en
Publication of WO1997049684A1 publication Critical patent/WO1997049684A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/50—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to ring nitrogen atoms
    • C07D241/52—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Definitions

  • the present invention relates to reagents useful as anticoagulants. More specifically, the invention relates to novel compounds that potentiates zinc ion inhibition of the activity of factor Vila or tissue factor-factor Vila complex, and pharmaceutical salts thereof. The invention further relates to pharmaceutical compositions, the preparation hereof, the use of the compounds of formula ia and lb as inhibitors of clotting activity, and methods of inhibiting clotting activity, tissue factor activity, and FVIIa activity.
  • Blood coagulation is a process consisting of a complex interaction of various blood components, or factors, which eventually gives rise to a fibrin clot.
  • the blood components which participate in what has been referred to as the coagulation "cascade” are proenzymes or zymogens, enzymatically inactive proteins, which are converted to proteolytic enzymes by the action of an activator, itself an activated clotting factor.
  • Coagulation factors that have undergone such a conversion and generally referred to as “active factors”, and are designated by the addition of the letter "a" to the name of the coagulation factor (e.g. factor Vila).
  • Activated factor X (“Xa”) is required to convert prothrombin to thrombin, which then converts fibrinogen to fibrin as a final stage in forming a fibrin clot.
  • the "intrinsic pathway” refers to those reactions that lead to thrombin formation through utilisation of factors present only in plasma.
  • a series of protease-mediated activations ultimately generates factor IXa, which, in conjunction with factor Villa, cleaves factor X into Xa.
  • An identical proteolysis is effected by factor Vila and its co-factor, tissue factor, in the "extrinsic pathway” of blood coagulation.
  • Tissue factor is a membrane bound protein and does not normally circulate in plasma.
  • Factor VII is a trace plasma glycoprotein that circulates in blood as a single- chain zymogen.
  • the zymogen is catalytically inactive (Williams et al., J. Biol. Chem. 264:7536-7543 (1989); Rao et al., Proc. Natl. Acad. Sci. USA. 85:6687-6691 (1988)).
  • Single-chain factor VII may be converted to two-chain factor Vila by factor Xa, factor Xlla, factor IXa, factor Vila or thrombin in vitro.
  • Factor Xa is believed to be the major physiological activator of factor VII.
  • factor VII is dependent on Vitamin K for its activity, which is required for the gamma -carboxylation of multiple glutamic acid residues that are clustered in the amino terminus of the protein. These gamma-carboxylated glutamic acids are required for the metal-associated interaction of factor VII with phospholipids.
  • zymogen factor VII The conversion of zymogen factor VII into the activated two-chain molecule occurs by cleavage of an internal Arg 1S2 -lle 153 peptide bond (Hagen et al., Proc. Natl. Acad. Sci. USA 83: 2412-2416 (1986); Thim et al., Biochem. 27:7785-7793 (1988) both of which are incorporated herein by references).
  • the two-chain factor Vila rapidly activates factor X or factor IX by limited proteolysis.
  • Factor Vila requires Ca 2* -ions and tissue factor for optimal activity. Apparently Ca 2+ is required for binding to tissue factor as well as for induction of an active conformation of the FVIIa molecule. Zn 2+ -ions have been shown to inhibit FVIIa activity, (Pedersen, et al.,: Thromb. Haemostas. 65:528-534 (1991); the normal concentration of free Zn 2+ -ions in the blood (15 ⁇ M) being 4-10 fold lower than the apparent Ki for zinc inhibition. It was suggested by these investigations that a histidine residue at position 241 immediately adjacent to the active site might be involved in coordination of the inhibitory Zn 2+ -ion.
  • Anticoagulants such as heparin, coumarin, derivatives of coumarin, indandione derivatives, thrombin inhibitors, factor Xa inhibitors, modified factor VII or other agents may be used.
  • Inhibition of coagulation is beneficial in a number of diseased states, for example during kidney dialysis, or to treat deep vein thrombosis, disseminated intravascular coagulation (DIC), and a host of other medical disorders.
  • heparin treatment or extracorporeal treatment with citrate ion may be used in dialysis to prevent coagulation during the course of treatment.
  • Heparin is also used in preventing deep vein thrombosis in patients undergoing surgery.
  • Treatment with heparin and other anticoagulants may, however, have undesirable side effects.
  • Available anticoagulants generally act throughout the body, rather than acting specifically at a clot site. Heparin, for example, may cause heavy bleeding.
  • heparin is rapidly cleared from the blood, necessitating frequent administrating. Because heparin acts as a cofactor for antithrombin III (AT III), and AT III is rapidly depleted in DIC treatment, it is often difficult to maintain the proper heparin dosage, necessitating continuous monitoring of AT III and heparin levels. Heparin is also ineffective if AT III depletion is extreme. Further, prolonged use of heparin may also increase platelet aggregation and reduce platelet count, and has been implicated in the development of osteoporosis. Indandione derivatives may also have toxic side effects.
  • AT III antithrombin III
  • anticoagulants comprise Thrombin- and factor Xa inhibitors derived from bloodsucking organisms.
  • Antithrombins, Hirudin, Hirulog and Hirugen are recombinant proteins or peptides derived from the leach Hirudo medicinalis whereas the factor Xa inhibitor antistatin and the derivative rTAP are tick-derived recombinant proteins.
  • Inhibitors of platelet aggregation such as monoclonal antibodies or synthetic peptides, which interfere with platelet receptor GPIIG/llia are also effective as anticoagulants. Bleeding complications are observed as an unwanted major disadvantage of antithrombin, antifactor Xa, as well as antiplatelet reagents.
  • Such anticoagulants comprise the physiological inhibitor TFPI (tissue factor pathway inhibitor) and modified factor VII (FVIlai), which is factor VII modified in such a way that it is catalytically inactive, but still binds to TF and compete with active factor Vila.
  • TFPI tissue factor pathway inhibitor
  • FVIlai modified factor VII
  • SMCs smooth muscle cells
  • treatment of atherosclerosis frequently includes the clearing of blocked vessels by angioplasty, endarterectomy or reduction atherectomy, or by bypass grafting, surgical procedures in which atherosclerotic plaques are compressed or removed through catheterization (angioplasty), stripped away from the arterial wall through an incision (endarterectomy) or bypassed with natural or synthetic grafts. These procedures remove the vascular endothelium, disturb the underlying intimal layer, and result in the death of medial SMCs.
  • This injury is followed by medial SMC proliferation and migration into the intima, which characteristically occurs within the first few weeks and up to six months after injury and stops when the overlying endothelial layer is re ⁇ established.
  • these lesions are composed of about 20% cells and 80% extracellular matrix.
  • Modified factor Vila (FVIlai) has been shown to effectively suppress the restenosis process possibly as a result of a decreased clot formation and thrombin generation initially after treatment of the constricted vessel.
  • the present invention fulfils this need by providing anticoagulants that act specifically at sites of injury, and further provides other related advantages such as its effect on the restenosis process.
  • the present invention has the additional advantage that it is a small synthetic molecule suitable for oral administration and for prophylactic treatment of atherosclerotic patients at risk for thrombosis. It has now surprisingly been found that Zn 2+ -ions exert their inhibitory action in competition with a stimulatory effect of Ca 2+ -ions.
  • Zinc is very unusual as a ligand for proteases of the chymotrypsin-like serine protease family, to which factor VII belongs. However, zinc is required for catalysis as an obligatory constituent of the active site of another class of proteolytic enzymes, the metalloproteases.
  • zinc chelators of the general formula la or lb have interesting pharmacological properties.
  • the compounds of this invention can be used in the treatment of deficiencies of blood clotting factors or the effect of inhibitors to blood clotting factors in mammals.
  • the present invention concerns the use of compounds having the general formula la
  • M 1 , M 2 , Y 1 , Y 2 , A, p, a and s are as defined below; or a pharmaceutically acceptable salt thereof, with the provisos that a+p+s is at least 1.
  • X, R1 and R2 are as defined below; and wherein the distance between C1 and C3 is from about 0.37nm to 0.77nm, e.g. 0.57 nm to about 0.67 nm; and pharmaceutically acceptable salts thereof; with the proviso that the compound is not L-cystine dihydroxamate.
  • Each of the above carbon atoms C 1 f C 2 and C 3 , in formula lb, are numbered so as to identify the specific carbon atom and shall not indicate anything else.
  • Figure 1 shows the effect of zinc and calcium ions on the activity of factor Vila (A) or the factor Vila-tissue factor complex (FVIIa-TF complex) (B).
  • Figure 2 shows the effect of zinc ions on TF-stimulated FVIIa activity in the absence and presence of cystin dihydroxamate.
  • Figure 3 shows the effect of zinc ions on TF-stimulated FVIIa activity in the absence and presence of 1-hydroxy-7-hydroxycarbamoyl quinoxaline-3,3(1H,4H)-dione (compound III).
  • Figure 4 shows the location of tissue factor binding region, the substrate binding pocket, and the calcium binding site in factor VII.
  • the present invention relates to a compound (zinc chelator) that po- tentiates zinc ion inhibition of the activity of factor Vila or tissue factor-factor Vila complex, with the proviso that the compound is not L-cystine dihydroxamate, 4,7-
  • the zinc chelator induces inhibition of blood coagulation.
  • the compound is a non-peptide.
  • L-cystine dihydroxamate means a compound of the formula
  • the present invention relates to a compound (zinc chelator) that potentiates zinc ion inhibition of the activity of factor Vila or tissue factor-factor Vila complex said compound being characterized by inhibiting factor Vila or tissue factor- factor Vila complex in the assay disclosed in example 4, with the proviso that the compound is not L-cystine dihydroxamate, 4,7-Dihydro-[4,7]phenanthroline- 1 ,2,3,8,9,10-hexaone-2,9-dioxime, 1 ,2,3-triazole-4,5-dicarbohydrazide and 5-(2- pyridyl)-1 ,2,4-triazole-3-carbohydrazide.
  • the zinc chelator induces inhibition of blood coagulation.
  • the compound is a non-peptide.
  • the present invention relates to a compound that binds to factor Vila and induces replacement of calcium ions with zinc ions in the serine protease domain of factor Vila, thereby inhibiting the activity of factor Vila or tissue factor- factor Vila complex, said compound being characterized by inhibiting factor Vila or tissue factor-factor Vila complex in the assay disclosed in example 4, with the proviso that the compound is not L-cystine dihydroxamate, 4,7-Dihydro- [4,7]phenanthroline-1 ,2,3,8,9, 10-hexaone-2,9-dioxime, 1 ,2,3-triazole-4,5- dicarbohydrazide and 5-(2-pyridyl)-1,2,4-triazole-3-carbohydrazide.
  • the zinc chelator induces inhibition of blood coagulation.
  • the compound is a non-peptide.
  • the compound binds to a site located in the serine protease domain of factor Vila, wherein said site is the calcium site located in a loop of the serine protease domain comprising amino acid residues 208-222 of factor Vila.
  • the compound has the formula III
  • first, second or third aspect of the invention it relates to compounds of the general formula lb
  • X is a chain, aliphatic or comprising hetero atoms as chain members; and R1 is hydrogen, an amino group (optionally substituted with methyl), or a methyl group; and R2 is hydrogen, or a methyl group; or X, in combination with C2, R1 , R2, N1 , and C3, forms a carbocyclic or heterocyclic system; and wherein the distance between C1 and C3 is from about 0.37 nm to about 0.77 nm; and pharmaceutically acceptable salts thereof.
  • the residue X may be a branched or unbranched carbon chain, or X may comprise carbon and/or nitrogen and/or sulphur and/or oxygen atoms (chain links) arranged in a branched or unbranched chain. Furthermore, X may comprise single and/or double bonds between chain links. X may also in combination with C2, R1 , R2, N1 , and C3 form a carbocyclic or heterocyclic system. This system may be monocyclic, bicyclic, or polycyclic with the proviso that the distance between the carbon atoms of the hydroxamate carbonyl groups (C1 and C3 in formula I) is from about 0.37 nm to about 0.77 nm.
  • the distance betwe- en C, and C 3 is from about 0.37nm to about 0.47nm. In a still further embodiment of the compound of general formula lb, the distance between C, and C 3 is from about 0.47nm to about 0.57nm.
  • the distance betwe ⁇ en C 1 and C 3 is from about 0.57nm to about 0.67nm.
  • the distance between C, and C 3 is from about 0.67nm to about 0.77nm.
  • the distance between C, and C 3 is from about 0.37nm to about 0.77nm, preferably from about 0.40nm to about 0.70nm, more preferred from about 0.40nm to about 0.65nm.
  • the compound of formula lb has the formula III
  • the compounds according to this invention e.g. such compounds having the general formulas la or lb have interesting pharmacological properties.
  • the compounds of this invention can be used to modulate and normalize an impaired haemostatic balance in mammals caused by deficiency or malfunction of blood clotting factors or their inhibitors.
  • the factor Vila and in particular the factor Vila/tissue factor activity plays an important role in the control of the coagulation cascade, and modulators of this key regulatory activity such as the present invention can be used in the treatment of coagulation-related diseased states.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to the first, second or third aspect of the invention, in combination with a pharmaceutical acceptable excipient and/ or carrier.
  • such compound is selected from 1-hydroxy-7-hydroxycarba- moylquinoxaline-2,3(1H,4H)-dione or Pyrazole-3,5-dicarbohydroxamic acid.
  • the composition further contains zinc ions.
  • zinc ions are meant to comprise the divalent cations, Zn 2+ .
  • Such zinc ions may be provided via zinc salts, e.g. ZnCI 2 or the like.
  • the pharmaceutical composition is administered by the oral route.
  • the route of administration of the compositions containing a compound of the invention may be any route which effectively transports the active compound to its site of action, such as transdermal, pulmonal, subcutane, rectal, etc.
  • the pharmaceutical composition according to the fourth aspect of the invention may be useful for modulating and normalizing an impaired haemostatic balance in a mammal.
  • the pharmaceutical composition may be useful for the treat- ment of coagulation-related diseased states.
  • the pharmaceutical composition may be useful as an inhibitor of blood coagulation in a mammal, as an inhibitor of clotting activity in a mammal, as an inhibitor of deposition of fibrin in a mammal, as an inhibitor of platelet deposition in a mammal, in the treatment of mammals suffering from deep vein thrombosis, pulmonary embolism, stroke, disse- minated intravascular coagulation (DIC), vascular restenosis, platelet deposition and 14
  • mammal is also intended to comprise a hu- man.
  • the present invention relates to use of a compound according to the first, second or third aspect of the invention for the preparation of a pharmaceutical composition for modulating and normalizing an impaired haemostatic balance in a mammal.
  • the invention relates to use of a compound according to the first, second or third aspect of the invention for the preparation of a pharmaceutical composition for treatment of coagulation-related diseased states.
  • the fifth aspect is for use as an inhibitor of blood coagu- lation in a mammal, or for use as an inhibitor of clotting activity in a mammal, or for use as an inhibitor of deposition of fibrin in a mammal, or for use as an inhibitor of platelet deposition in a mammal.
  • a compound according to the first, second or third aspect of the invention for the preparation of a pharmaceutical composition, for treatment of mammals suffering from deep vein thrombosis, pulmonary embolism, stroke, disseminated intravascular coagulation (DIC), vascular restenosis, platelet deposition and associated disorders and myocardial infarction, and in the prophylactic treatment of mammals with atherosclerotic vessels at risk for thrombosis.
  • DIC disseminated intravascular coagulation
  • vascular restenosis vascular restenosis
  • platelet deposition and associated disorders and myocardial infarction and in the prophylactic treatment of mammals with atherosclerotic vessels at risk for thrombosis.
  • composition further contains zinc ions.
  • the invention in a sixth aspect relates to a method of modulating and normalizing an impaired haemostatic balance in a mammal, which method comprises administering an effective amount of a compound according to the first, second or third aspect of the invention, optionally in combination with a pharmaceutical acceptable excipient and/ or carrier to the mammal in need of such a treatment.
  • a pharmaceutical acceptable excipient and/ or carrier e.g. 1-hydroxy-7-hydroxycarbamoylquinoxaline-2,3(1 H,4H)-dione or Pyrazole-3,5- dicarbohydroxamic acid.
  • the method further comprises administering zinc ions.
  • the present invention also relates to a method for treatment of coagulation-related diseased states in a mammal, which method comprises administering an effective amount of a compound according to the first, second or third aspect of the invention, optionally in combination with a pharmaceutical acceptable excipient and/ or carrier to the mammal in need of such a treatment.
  • a pharmaceutical acceptable excipient and/ or carrier e.g. 1-hydroxy-7- hydroxycarbamoylquinoxaline-2,3(1 H,4H)-dione or Pyrazole-3,5-dicarbohydroxamic acid.
  • the method further comprises administering zinc ions.
  • the present invention also relates to a method for treatment of mammals suffering from deep vein thrombosis, pulmonary embolism, stroke, disseminated intravascular coagulation (DIC), vascular restenosis, platelet deposition and associated disorders and myocardial infarction, and in the prophylactic treatment of mammals with atherosclerotic vessels at risk for thrombosis, which method comprises administering a therapeutically effective amount of a compound according to the first, second or third aspect of the invention, optionally in combination with a pharmaceutical acceptable excipient and/ or carrier to the mammal in need of such a treatment.
  • a pharmaceutical acceptable excipient and/ or carrier e.g. 1-hydroxy-7-hydroxycarbamoylquinoxaline- 2,3(1 H,4H)-dione or Pyrazole-3,5-dicarbohydroxamic acid.
  • the method further comprises administering zinc ions.
  • compositions according to the present invention should be determined by those skilled in the art.
  • the daily dose to be administered in therapy can be determined by a physician and will depend on the 16
  • the daily dose comprises an effective amount (i.e. a therapeutically effective amount) of a compound according to the invention wherein the amount can be determined by a physician and will depend on the particular compound employed, on the route of administration and on the age and the condition of the patient.
  • a convenient daily dosage can be in the range of from about 0.1 ⁇ mol to about 0.2 mmol of the active ingredient.
  • the pharmaceutical composition according to the fourth aspect of the invention may be useful for modulating and normalizing an impaired haemostatic balance in a mammal.
  • the pharmaceutical composition may be useful for the treat ⁇ ment of coagulation-related diseased states.
  • the pharmaceutical composition may be useful as an inhibitor of blood coagulation in a mammal, as an inhibitor of clotting activity in a mammal, as an inhibitor of deposition of fibrin in a mammal, as an inhibitor of platelet deposition in a mammal, in the treatment of mammals suffering from deep vein thrombosis, pulmonary embolism, stroke, disse ⁇ minated intravascular coagulation (DIC), vascular restenosis, platelet deposition and associated disorders and myocardial infarction, and in the prophylactic treatment of mammals with atherosclerotic vessels at risk for thrombosis.
  • DIC intravascular coagulation
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the general formula la
  • M 1 is heteroaryl, a group of the formula z 3 o
  • M 2 2 is heteroaryl, or a group of the formula O 7 2
  • A is aryl or heteroaryl, p, a and s independently of each other are 0 or 1 ; or a pharmaceutically acceptable salt thereof; with the provisos that a+p+s is at least 1 ; in combination with a pharmaceutical ac ⁇ ceptable excipient and/ or carrier.
  • M 1 and M 2 are in- dependently of each other pyridinyl, such as pyridin-2-yl. In a preferred embodiment only one of M 1 and M 2 are pyridinyl, such as pyridin-2-yl.
  • the distance between C, and C 2 is from about 0.37nm to about 0.47nm.
  • the di- stance between C, and C 2 is from about 0.47nm to about 0.57nm.
  • the distance between C, and C 2 is from about 0.57nm to about 0.67nm.
  • the di ⁇ stance between C, and C 2 is from about 0.67nm to about 0.77nm.
  • the distance between C, and C 2 is from about 0.37nm to about 0.77nm, preferably from about 0.40nm to about 0.70nm, more preferred from about 0.40nm to about 0.65nm.
  • Z 1 , Z 2 , Z 3 and Z 4 are independently of each other hydrogen, methyl, hydroxy, amino or a va ⁇ lence bond attached to A.
  • Z ⁇ Z 2 , Z 3 and Z 4 are independently of each other hydrogen, hydroxy, amino or a valence bond attached to A.
  • the com ⁇ pound is selected from: 1-hydroxy-7-hydroxycarbamoylquinoxaline-2,3(1H,4H)-dione, having the formula I
  • composition further contains zinc ions.
  • zinc ions may be provided via zinc salts, e.g. ZnCI 2 or the like.
  • the pharmaceutical composition is administered by the oral route.
  • the route of administration of the compositions containing a compound of the invention may be any route which effectively transports the active compound to its site of action, such as transdermal, pulmonal, subcutane, rectal, etc.
  • the pharmaceuti- cal composition may be useful for modulating and normalizing an impaired haemo- static balance in a mammal.
  • the pharmaceutical composition may be useful for the treatment of coagulation-related diseased states.
  • the pharmaceutical composition may be useful as an inhibitor of blood coagulation in a mammal, or as an inhibitor of clotting activity in a mammal, or as an inhibitor of deposition of fibrin in a mammal, or as an inhibitor of platelet deposition in a mammal.
  • the pharmaceutical composition may be useful in the treatment of mammals suffering from deep vein thrombosis, pulmonary embolism, stroke, disseminated intravascular coagulation (DIC), vascular restenosis, platelet deposition and associated disorders and myocardial infarction, and in the prophylactic treatment of mammals with atherosclerotic vessels at risk for thrombosis.
  • DIC disseminated intravascular coagulation
  • vascular restenosis vascular restenosis
  • platelet deposition and associated disorders and myocardial infarction and in the prophylactic treatment of mammals with atherosclerotic vessels at risk for thrombosis.
  • M 1 is heteroaryl, a group of the formula Z 3 O
  • M 2 is heteroaryl, or a group of the formula rmula
  • A is aryl such as phenyl or heteroaryl such as pyrazolyl, 1 ,2,3-triazolyl, or 1 ,2,4- triazolyl, p, a and s independently of each other are 0 or 1 ; or a pharmaceutically acceptable salt thereof; with the provisos that a+p+s is at least 1 ; in the preparation of a medicament for mo ⁇ dulating and normalizing an impaired haemostatic balance in a mammal.
  • the compound of formula la may be useful in the preparation of a pharmaceuti ⁇ cal composition for treatment of coagulation-related diseased states.
  • it may be useful for the preparation of a pharmaceutical composition, for use as an in ⁇ hibitor of blood coagulation in a mammal, or for use as an inhibitor of clotting activity in a mammal, or for use as an inhibitor of deposition of fibrin in a mammal, or for use as an inhibitor of platelet deposition in a mammal.
  • the compound of formula la may be useful for the preparation of a pharmaceutical composition, for treatment of mammals suffering from deep vein thrombosis, pulmonary embolism, stroke, disseminated intravascular coagulation (DIC), vascular restenosis, platelet deposition and associated disorders and myocardial infarction, and in the prophylactic treatment of mammals with atherosclerotic vessels at risk for thrombosis.
  • DIC disseminated intravascular coagulation
  • vascular restenosis vascular restenosis
  • platelet deposition and associated disorders and myocardial infarction and in the prophylactic treatment of mammals with atherosclerotic vessels at risk for thrombosis.
  • said composition further contains zinc ions.
  • the present invention also relates to a method of modulating and normalizing an impaired haemostatic balance in a mammal, which method comprises administering an effective amount of a compound of formula la, in combination with a pharmaceutical acceptable excipient and/ or carrier to the mammal in need of such a treatment.
  • a compound of formula la may be selected from the compounds
  • the present invention relates to a method for treatment of coagulation- related diseased states in a mammal, which method comprises administering an ef ⁇ fective amount of a compound of formula la, in combination with a pharmaceutical acceptable excipient and/ or carrier to the mammal in need of such a treatment.
  • the method is for treatment of mammals suffering from deep vein thrombosis, pulmonary embolism, stroke, disseminated intravascular coagulation (DIC), vascular restenosis, platelet deposition and associated disorders and myocardial infarction, and in the prophylactic treatment of mammals with atherosclerotic vessels at risk for thrombosis, which method comprises administering a therapeutically effective amount of a compound of formula la, in combination with a pharmaceutical acceptable excipient and/ or carrier to the mammal in need of such a treatment.
  • DIC disseminated intravascular coagulation
  • the method further comprises administering zinc ions.
  • the present invention relates to a complex comprising a compound according to any one of the claims 1-15 or a compound of formula la and zinc ions.
  • a compound being e.g. 1-hydroxy-7-hydroxycarbamoylquinoxaline- 2,3(1 H,4H)-dione or pyrazole-3,5-dicarbohydroxamic acid.
  • the complex of the invention may be useful for modulating and normalizing an impaired haemostatic balance in a mammal.
  • it may be useful for the treatment of coagulation-related diseased states.
  • the complex of the invention may be useful as an inhibitor of blood coagulation in a mammal, or as an inhibitor of clotting activity in a mammal, or as an inhibitor of deposition of fibrin in a mammal, or as an inhibitor of platelet deposition in a mammal.
  • the complex of the invention may be useful in the treatment of mammals suffering from deep vein thrombosis, pulmonary embolism, stroke, disseminated intravascular coagulation (DIC), vascular restenosis, platelet deposition and associated disorders and myocardial infarction, and in the prophylactic treatment of mammals with atherosclerotic vessels at risk for thrombosis.
  • DIC disseminated intravascular coagulation
  • vascular restenosis vascular restenosis
  • platelet deposition and associated disorders and myocardial infarction and in the prophylactic treatment of mammals with atherosclerotic vessels at risk for thrombosis.
  • the invention relates to a method for inhibiting tissue factor activity in a mammal which method comprises administering an effective amount of a compound according to any one of claims 1-15 or a compound of formula la, in combination with 26
  • One embodiment hereof further comprises administering zinc ions.
  • the invention relates to a method for inhibiting factor Vll activity by substantially reducing the ability of activated factor Vll to catalyze tissue factor- enhanced activation of factors X and IX comprising administering a compound according to any one of the claims 1-15 or a compound of formula la, in combination with a pharmaceutical acceptable excipient and/ or carrier to a mammal in need of such a treatment.
  • One embodiment hereof further comprises administering zinc ions.
  • the invention also relates to a method for substantially inhibiting the binding of FVII to tissue factor comprising replacing FVII-bound calcium ions with zinc ions, which method comprises administering an effective amount of a compound according to any one of claims 1-15 or a compound of formula la, in combination with a pharma- ceutical acceptable excipient and/ or carrier to the mammal in need of such a treat ⁇ ment.
  • One embodiment hereof further comprises administering zinc ions.
  • the invention also concerns a method of detecting a zinc chelator which potentiates zinc ion inhibition of factor Vila or factor Vila/tissue factor activity, comprising testing one or more specific compounds in the assay disclosed in example 4.
  • a zinc chelator which potentiates zinc ion inhibition of factor Vila or factor Vila/tissue factor activity, comprising testing one or more specific compounds in the assay disclosed in example 4.
  • Such compound may be selected from compounds of formula la or lb, or from any compound of non-peptide origin.
  • the invention also relates to a method of substantially reducing the binding of FVII to tissue factor by replacing FVII-bound Ca 2+ with Zn 2+ , and the use of a Ca 2+ binding site in FVII to substantially reduce the binding of FVII to tissue factor.
  • compositions of the invention are particularly useful in methods for treating patients when formulated into pharmaceutical compositions, where they may be 27
  • compositions of the invention are particular useful in prophylactic treatment of patients with atherosclerotic vessels at risk for thrombosis.
  • the compositions can also be used to inhibit vascular restenosis and platelet deposition and associated disorders.
  • compositions typically for oral administration to humans will comprise one or more compounds of the invention, optionally in combination with zinc salts, and pharmaceutically acceptable carriers and buffers.
  • Examples of pharmaceutically acceptable salts are pharmaceutically acceptable acid addition salts with non-toxic acids, either inorganic acids such as hydrochloric acid, sulphuric acid and phosphoric acid, or organic acids such as formic acid, acetic acid, propionic acid, succinic acid, gluconic acid, lactic acid, citric acid, ascorbic acid, benzoic acid, embonic acid, methanesulphonic acid and malonic acid.
  • inorganic acids such as hydrochloric acid, sulphuric acid and phosphoric acid
  • organic acids such as formic acid, acetic acid, propionic acid, succinic acid, gluconic acid, lactic acid, citric acid, ascorbic acid, benzoic acid, embonic acid, methanesulphonic acid and malonic acid.
  • the compounds of formula la and/or lb are prepared by methods known p_ej se by the skilled art worker, such as exemplified by the preparation of compound III in example No. 1.
  • compositions which comprise at least one compound of formula I or a pharmaceutically acceptable acid addition salt thereof in connection with a pharmaceutically acceptable carrier.
  • Such compositions may be in the form of powders, solutions, or suspensions, which may or may not be divided in unit dosage form or in the form of capsules or tablets.
  • a preferred composition is in the form of an composition for oral administering.
  • the pharmaceutical compositions of this invention may comprise carriers, diluents, absorption enhancers, tablet disintegrating agents and other ingredients which are conventionally used in the art.
  • the powders and tablets preferably contain from 5 to 99%, more preferred from 10 to 90 of the active ingredient.
  • solid carriers are magnesium carbonate, magnesium stearate, dextrin, lactose, sugar, talc, gelatin, pectin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting waxes and cocoa butter.
  • Liquid compositions include sterile solutions, suspensions and emulsions suitable for parenteral injection.
  • compositions of this invention are prepared by methods known Q ⁇ se by the skilled art worker.
  • the chocolate-brown reaction mixture was poured into a Buchner funnel and washed extensively with methanol, water, methanol, dichloromethane, until the resin was colorless, c)
  • the resin was suspended in ethanol (70 mL), anhydrous hydrazine (8 mL) was added, and the mixture was shaken at 25°C for 16 h.
  • the resin was washed extensively with methanol, dichloromethane, methanol and dried; yield 9.50 g (95%).
  • Fig. 1 Effect of zinc ions on the amidolytic activity of (A) factor Vila or (B) factor Vila /tissue factor in the presence of various concentrations of calcium ions. Activity was measured at room temperature with the chromogenic substrate S2288 (H-D-lle-Pro-Arg-p-nitroanilide) as the change in absorbance at 405 nm.
  • the buffer contained: 0.4 mM S2288, 50 mM TrisCI, 100 mM NaCl, 0.05 % Tween 20, pH 7.4.
  • Fig. 2 shows that the effect of zinc ions to abolish FVIIa-TF complex formation is profoundly potentiated by the zinc chelator, cystindihydroxamate.
  • Fig.2 Effect of zinc ions on TF-stimulated factor Vila activity in the absence (control) and presence of 0.2 mM cystin dihydrxamate.
  • Factor Vila activity was measured with the chromogenic substrate S2288 (H-D-lle-Pro-Arg-p-nitroanilide).
  • the activity of 10 nM FVIIa in the presence of 50 nM TF ⁇ was measured in buffer containing 50 mM TrisCI pH 7.4 0.1 M NaCl, 1 mM CaCI 2 , 0.05 % Tween 20 and 0.4 mM S2288.
  • the activity was measured at room temprature as the change in absorbance at 405 nm.
  • Example 5 The activity was measured at room temprature as the change in absorbance at 405 nm. Example 5.
  • Fig. 3 Effect of zinc ions on TF-stimulated FVIIa activity in the absence (control) and presence of 0.2 mM 1-hydroxy-7-hydroxycarbamoyl quinoxaline-3,3(1H,4H)-dione. The experiments were performed as described in Example 3.

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Abstract

Composés représentés par la formule générale (Ib) et leurs sels pharmaceutiquement acceptables. Dans ladite formule, X représente une chaîne aliphatique ou comprenant des hétéroatomes en tant qu'éléments de la chaîne; R1 représente hydrogène, un groupe amino (éventuellement substitué par méthyle) ou un groupe méthyle; R2 représente hydrogène ou un groupe méthyle; ou X, en combinaison avec C2, R1, R2, N1 et C3, constitue un système carbocyclique ou hétérocyclique; et dans laquelle la distance entre C1 et C3 est d'environ 0,37 nm à 0,77 nm environ, par exemple d'environ 0,57 nm à 0,67 nm environ. Ces composés sont des agents chélatants du zinc. Ces composés présentent des propriétés anticoagulantes dues à une interaction inhibitrice avec le facteur VII et le taux sérique Zn2+. Ces agents chélatants du zinc se fixent au facteur VIIa et provoquent le remplacement des ions calcium par des ions zinc dans le domaine de sérine protéase du facteur VIIa, ce qui inhibe l'activité du facteur VIIa ou du complexe constitué par le facteur tissulaire et le facteur VIIa. Ces composés sont utiles pour le traitement de déficiences de facteurs de coagulation sanguine ou des effets d'inhibiteurs de ces facteurs de coagulation. L'invention concerne également des procédés servant à inhiber l'activité de coagulation.
PCT/DK1997/000275 1996-06-24 1997-06-23 Reactif se fixant au facteur vii WO1997049684A1 (fr)

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US6180625B1 (en) 1998-03-24 2001-01-30 Novo Nordisk A/S Heterocyclic compounds regulating clotting
EP1193248A1 (fr) * 2000-09-30 2002-04-03 Aventis Pharma Deutschland GmbH Dérivés de malonamide et d'ester malonamique possédant une activité antithrombotique, leur préparation et leur emploi

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EP1005361B1 (fr) * 1997-07-18 2010-01-06 Novo Nordisk Health Care AG Utilisation de fvii ou fviiai pour le traitement de perturbations fonctionelles endotheliaux respectivement pour l'inhibition de l'angiogenese
WO2003015715A2 (fr) * 2001-08-20 2003-02-27 Bristol-Myers Squibb Company Derives de tetrahydroquinoline utilises comme agents antithrombotiques
EP1539762A2 (fr) * 2002-06-26 2005-06-15 Bristol-Myers Squibb Company Pyrimidinones bicycliques inhibiteurs de la cascade de coagulation
AU2003243657A1 (en) * 2002-06-26 2004-01-19 Bristol-Myers Squibb Company Amino-bicyclic pyrazinones and pyridinones
EP2940072B1 (fr) * 2005-08-09 2020-05-27 Kraton Chemical, LLC Compositions de caoutchouc contenant des agents collants améliorés
JP2018531213A (ja) 2015-03-13 2018-10-25 フォーマ セラピューティクス，インコーポレイテッド Ｈｄａｃ８阻害剤としてのアルファ−シンナミド化合物及び組成物
US10029995B2 (en) 2015-09-03 2018-07-24 Forma Therapeutics, Inc. [6,6] fused bicyclic HDAC8 inhibitors

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US6180625B1 (en) 1998-03-24 2001-01-30 Novo Nordisk A/S Heterocyclic compounds regulating clotting
EP1193248A1 (fr) * 2000-09-30 2002-04-03 Aventis Pharma Deutschland GmbH Dérivés de malonamide et d'ester malonamique possédant une activité antithrombotique, leur préparation et leur emploi
WO2002028823A1 (fr) * 2000-09-30 2002-04-11 Aventis Pharma Deutschland Gmbh Derives de malonamide et d'ester malonamique possedant une activite antithrombotique, et preparation et utilisation de ceux-ci
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US7153876B2 (en) 2000-09-30 2006-12-26 Sanofi-Aventis Deutschland Gmbh Malonamid and malonamic ester derivatives with antithrombotic activity, their preparation, and their use

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